The pol gene of the human immunodeficiency virus (HIV) encodes three viral enzymes, reverse transcriptase, protease and integrase, which are critical for the replication of HIV. This project is focused on the discovery of inhibitors of one of these viral enzymes, HIV reverse transcriptase (HIV RT). The broad objectives are to contribute to the chemistry and biochemistry of conceptually new nucleosides and nucleotides with useful therapeutic potential against the infectivity of HIV. These novel compounds, with stereochemically defined surrogate carbohydrate components, that are regioisomeric with the natural nucleosides and nucleotides, are referred to as isonucleosides and isonucleotides. A compelling rationale for this investigation comes from the discovery in this project of a potently anti-HIV active compound, (S,S)-isodideoxyadenosine IsoddAj. IsoddA 5'-triphosphate is a powerful inhibitor of HIV RT (K 16 nM). This renewal proposal seeks to expand the successful work of the current project to include cyclic monophosphate (MP) pro-drugs (cyclo Sal MPs) and hydrolytically stable phosphonyl derivatives in order to deliver the MPs or their isosteres directly inside the cell. In addition, new classes of isonucleosides with multiple supporting rationale for anti-HIV activity are proposed. The synthetic work will involve the development of approaches to the novel, chiral isodideoxynucleosides and their purification and complete characterization by magnetic resonance, mass spectral, and X-ray methods. Collaborative antiviral studies on the target compounds and pro-drug forms will be carried out against HIV-l and HIV-2, and important drug-resistant HIV mutants. Data on inhibition of the cytopathic effect of HIV, on inhibition of HIV RT, on inhibition of proviral DNA synthesis, on host cell cytotoxicity including inhibition of cellular DNA polymerases a, and y, and on therapeutic indexes will be determined and analyzed. Cellular combination drug studies, particularly those having the potential for synergistic inhibition of HIV infectivity, are also planned.